The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction

Debbie Grønlund; Jakob L. Poulsen; Klaus Krogh; Christina Brock; Donghua Liao; Hans Gregersen; Asbjørn M. Drewes; Anne E. Olesen

doi:10.1016/j.ejps.2018.02.008

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction

Debbie Grønlund, Jakob L. Poulsen, Klaus Krogh, Christina Brock, Donghua Liao, Hans Gregersen, Asbjørn M. Drewes, Anne E. Olesen^*

^*Corresponding author for this work

6 Citations (Scopus)

Abstract

Background and aims: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. Methods: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. Results: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (−45.9 vs −38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). Conclusions: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

Original language	English
Journal	European Journal of Pharmaceutical Sciences
Volume	117
Pages (from-to)	187-192
Number of pages	6
ISSN	0928-0987
DOIs	https://doi.org/10.1016/j.ejps.2018.02.008
Publication status	Published - 2018

Keywords

Anal sphincter
Constipation
Functional lumen imaging probe
Naloxegol
Opioid-induced bowel dysfunction
Opioids
Recto-anal inhibitory reflex

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10.1016/j.ejps.2018.02.008

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@article{550881f149a94d9c877461b04786e61a,

title = "The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction",

abstract = "Background and aims: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. Methods: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. Results: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (−45.9 vs −38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). Conclusions: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.",

keywords = "Anal sphincter, Constipation, Functional lumen imaging probe, Naloxegol, Opioid-induced bowel dysfunction, Opioids, Recto-anal inhibitory reflex",

author = "Debbie Gr{\o}nlund and Poulsen, {Jakob L.} and Klaus Krogh and Christina Brock and Donghua Liao and Hans Gregersen and Drewes, {Asbj{\o}rn M.} and Olesen, {Anne E.}",

year = "2018",

doi = "10.1016/j.ejps.2018.02.008",

language = "English",

volume = "117",

pages = "187--192",

journal = "European Journal of Pharmaceutical Sciences",

issn = "0928-0987",

publisher = "Elsevier",

}

TY - JOUR

T1 - The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction

AU - Grønlund, Debbie

AU - Poulsen, Jakob L.

AU - Krogh, Klaus

AU - Brock, Christina

AU - Liao, Donghua

AU - Gregersen, Hans

AU - Drewes, Asbjørn M.

AU - Olesen, Anne E.

PY - 2018

Y1 - 2018

N2 - Background and aims: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. Methods: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. Results: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (−45.9 vs −38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). Conclusions: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

AB - Background and aims: Opioid treatment interferes with anal sphincter function and its regulation during defecation. This may result in straining, incomplete evacuation, and contribute to opioid-induced bowel dysfunction (OIBD). Employing an experimental model of oxycodone-induced OIBD, we hypothesized that co-administration of the peripherally acting μ-opioid antagonist naloxegol would improve anal sphincter function in comparison to placebo. Methods: In a double-blind randomized crossover trial, 24 healthy males were assigned to a six-day treatment of oral oxycodone 15 mg twice daily in combination with either oral naloxegol 25 mg once daily or placebo. At baseline and at day 6, anal resting pressure and the recto-anal inhibitory reflex (RAIR) were evaluated using manometry and rectal balloon distension. Furthermore, the functional lumen imaging probe was used to measure distensibility of the anal canal. Gastrointestinal symptoms were assessed with the Patient Assessment of Constipation Symptom (PAC-SYM) questionnaire and the Bristol Stool Form Scale. Results: During oxycodone treatment, naloxegol improved RAIR-induced sphincter relaxation by 15% (−45.9 vs −38.8 mm Hg; P < 0.01). No differences in anal resting pressure and anal canal distensibility were found between treatments (all P > 0.5). Naloxegol improved PAC-SYM symptoms (mean score over days; 2.6 vs 4.5, P < 0.001) and improved stool consistency scores (mean score over days; 3.3 vs 2.9, P < 0.01). Conclusions: In this experimental model of OIBD, naloxegol improved the RAIR and reduced gastrointestinal symptoms. Hence, in contrast to conventional laxatives, naloxegol may regulate opioid-induced anal sphincter dysfunction and facilitate the defecation process.

KW - Anal sphincter

KW - Constipation

KW - Functional lumen imaging probe

KW - Naloxegol

KW - Opioid-induced bowel dysfunction

KW - Opioids

KW - Recto-anal inhibitory reflex

U2 - 10.1016/j.ejps.2018.02.008

DO - 10.1016/j.ejps.2018.02.008

M3 - Journal article

C2 - 29432808

AN - SCOPUS:85042504710

SN - 0928-0987

VL - 117

SP - 187

EP - 192

JO - European Journal of Pharmaceutical Sciences

JF - European Journal of Pharmaceutical Sciences

ER -

The impact of naloxegol on anal sphincter function - Using a human experimental model of opioid-induced bowel dysfunction

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Keywords

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